Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9
Open Access
- 1 July 2008
- journal article
- Published by Elsevier BV
- Vol. 283 (29), 19879-19887
- https://doi.org/10.1074/jbc.m802848200
Abstract
Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation of MAPKs and NF-κB, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.Keywords
This publication has 78 references indexed in Scilit:
- TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccinesNature, 2008
- DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune responseNature, 2007
- An Atomic Model of the Interferon-β EnhanceosomeCell, 2007
- TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniaeCellular Immunology, 2007
- Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A StreptococcusProceedings of the National Academy of Sciences of the United States of America, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006
- Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune ResponseImmunity, 2006
- ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunityNature Immunology, 2005
- TLR9 signals after translocating from the ER to CpG DNA in the lysosomeNature Immunology, 2004
- A Conserved p38 MAP Kinase Pathway in Caenorhabditis elegans Innate ImmunityScience, 2002